Polymorphonuclear leukocytes require a contractile apparatus, a force-generating motor for shape changes, movement and phagocytosis. A major component of this motor is actin. Actin can exist in at least two states, as monomers and as filaments. The present studies explore the regulation of actin conversion from monomers to filaments, the possible first step in force generation. A child with severe recurrent infections and depressed granulocyte chemotaxis and phagocytosis was shown to have a defect in cytoplasmic actin filament formation. More recently, we have demonstrated this polymerization defect is an autosomal recessive disorder caused by an increased susceptibility of actin to endogenous protease cleavage. In addition to this irreversible mechanism for inhibiting actin filament formation, we have also found a 65,000 dalton granulocyte protein which reversible blocks actin polymerization. Inhibition is reversed by high potassium concentration. Evidence for physiologic and pathologic alterations in actin's state will be examined. I plan to: 1) fully study the properties of this newly discovered actin polymerization inhibitor, using physicochemical techniques; 2) further characterize the molecular basis of the recessive actin polymerization defect; 3) investigate the effects of endogenous protease activity on the state of actin. These studies will attempt to relate the structure and function of actin to human disease. Although focused on polymorphonuclear motility important in infection, inflammation and tissue repair, results clarifying mechanisms by which actin filament formation can be regulated should be applicable to cell division, secretion and development.